The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models
<p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by degeneration of both upper and lower motor neurons. Most ALS occurs in a sporadic manner, though 5-10% is familial. Fused in sarcoma (FUS) is an RNA binding protein, and mutations in the FUS gene are respon...
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| Format: | Thesis |
| Language: | English |
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2015
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| _version_ | 1824459246065942528 |
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| author | Kent, L |
| author2 | Talbot, K |
| author_facet | Talbot, K Kent, L |
| author_sort | Kent, L |
| collection | OXFORD |
| description | <p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by degeneration of both upper and lower motor neurons. Most ALS occurs in a sporadic manner, though 5-10% is familial. Fused in sarcoma (FUS) is an RNA binding protein, and mutations in the FUS gene are responsible for approximately 4% of familial and &LT;1% of sporadic ALS cases. This work uses <em>in vitro</em> and <em>in vivo</em> models to examine the cellular effects of FUS mutations and the potential mechanisms of motor neuron toxicity.</p> <p>The first section describes a family with a severe clinical form of ALS due to a FUS truncation mutation p.G504Wfs&ast;12. This mutation demonstrates a severe phenotype <em>in vitro</em>, with mislocalisation of mutant FUS from the nucleus to the cytoplasm, and co-localisation with stress granules. Comparing these results with other mutations highlights the correlation between FUS mislocalisation and clinical phenotype, suggesting that the distribution of FUS plays a role in the pathogenesis of ALS.</p> <p>The next section explores the phenotype of primary motor neurons from a FUS BAC transgenic mouse model expressing low levels of wild-type or P525L human FUS. P525L-FUS shows marked mislocalisation to the cytoplasm and co-localisation with stress granules, with evidence of reduced survival and alterations in stress granule dynamics. This suggests that motor neurons expressing mutant FUS show inherent vulnerability.</p> <p>The final section explores transcript levels and alternative splicing in both FUS and TDP-43 BAC transgenic mouse models. Key proteins such as TDP-43, FUS and SMN show alterations in mRNA levels in CNS tissue, and some subtle splicing alterations are described.</p> <p>This work suggests that mutations in <em>FUS</em> are likely to affect motor neurons even when expressed at very low levels. Alterations in FUS distribution, stress granule dynamics, and regulation of transcription may all play a part in conferring a susceptibility to developing ALS.</p> |
| first_indexed | 2025-02-19T04:38:44Z |
| format | Thesis |
| id | oxford-uuid:f0968f9d-db01-4ace-bbd7-fc43319e19ea |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:38:44Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | oxford-uuid:f0968f9d-db01-4ace-bbd7-fc43319e19ea2025-02-06T08:52:11ZThe molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro modelsThesishttp://purl.org/coar/resource_type/c_db06uuid:f0968f9d-db01-4ace-bbd7-fc43319e19eaEnglishORA Deposit2015Kent, LTalbot, K<p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by degeneration of both upper and lower motor neurons. Most ALS occurs in a sporadic manner, though 5-10% is familial. Fused in sarcoma (FUS) is an RNA binding protein, and mutations in the FUS gene are responsible for approximately 4% of familial and &LT;1% of sporadic ALS cases. This work uses <em>in vitro</em> and <em>in vivo</em> models to examine the cellular effects of FUS mutations and the potential mechanisms of motor neuron toxicity.</p> <p>The first section describes a family with a severe clinical form of ALS due to a FUS truncation mutation p.G504Wfs&ast;12. This mutation demonstrates a severe phenotype <em>in vitro</em>, with mislocalisation of mutant FUS from the nucleus to the cytoplasm, and co-localisation with stress granules. Comparing these results with other mutations highlights the correlation between FUS mislocalisation and clinical phenotype, suggesting that the distribution of FUS plays a role in the pathogenesis of ALS.</p> <p>The next section explores the phenotype of primary motor neurons from a FUS BAC transgenic mouse model expressing low levels of wild-type or P525L human FUS. P525L-FUS shows marked mislocalisation to the cytoplasm and co-localisation with stress granules, with evidence of reduced survival and alterations in stress granule dynamics. This suggests that motor neurons expressing mutant FUS show inherent vulnerability.</p> <p>The final section explores transcript levels and alternative splicing in both FUS and TDP-43 BAC transgenic mouse models. Key proteins such as TDP-43, FUS and SMN show alterations in mRNA levels in CNS tissue, and some subtle splicing alterations are described.</p> <p>This work suggests that mutations in <em>FUS</em> are likely to affect motor neurons even when expressed at very low levels. Alterations in FUS distribution, stress granule dynamics, and regulation of transcription may all play a part in conferring a susceptibility to developing ALS.</p> |
| spellingShingle | Kent, L The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title | The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title_full | The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title_fullStr | The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title_full_unstemmed | The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title_short | The molecular pathogenesis of FUS mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| title_sort | molecular pathogenesis of fus mutations in amyotrophic lateral sclerosis using in vivo and in vitro models |
| work_keys_str_mv | AT kentl themolecularpathogenesisoffusmutationsinamyotrophiclateralsclerosisusinginvivoandinvitromodels AT kentl molecularpathogenesisoffusmutationsinamyotrophiclateralsclerosisusinginvivoandinvitromodels |